Compounds of the etio-cholanic acid series and process of making same



Patented Aug. 6, 1940 COMPOUNDS F PATENT OFFICE THE ETIO-CHOLANIC ACID SERIES AND PROCESS OF MAKING v Max Hartmann, Riehen, and Albert Wettstein,

Basel, Switzerland,

assignors to the firm Society of Chemical Industry in Basle, Basel,

Switzerland No Drawing, Application May 3, 1938, SerialNo.

, 205,850. In Switzerland May 5, 1937 I 20 Claims. (01. 260-397) This invention relates to an improvement in or modification of that described in application Serial No. 131,518 filed March 17, 1937.' That specification describes av manufacture of ketones in which, inter alia, the double linking of nuclear .saturatedgenins of the heart -glucosides or their derivatives having anunsaturated u-lactone ring as a side chain is opened by oxidation and the pketocarboxylic acid thus produced is subjected to ketone scission. I

The present invention relates to the manufacture of saturated or unsaturated compounds of the etio-cholanic acid series by treating a nuclear saturated or unsaturatedgeninof a'heart glucoside or a. derivative thereof containing in the 17-position a aw-unsaturated a-lactone .ring, With an oxidizing agent, if desired with temporary protection of secondary nu'clear'hydroxyl groups and nuclear. double linkings, and ifj desired subjecting to acid scission-the fi-ketocarboxylic acid may be treated with an agent for eliminating water for the purpose of removing in stages or- 25 completely the tertiary hydroxyl groups present,

and the double linkings thus produced may be hydrogenated if desired.

, It is to be understood that under the expression saturated or unsaturated compounds of'the 3 etio-cholanic acid series are included quite generally 10,13 dimethyl cyclopentanopolyhydrophenanthrene-1'7-carboxylic acids with any steric configuration and if desired containing .further substituents.

85 Suitable parent material s. are,for example,

40 fying (for example with triarylcarbinols or with monoor polysaccharides) orby partial or complete elimination of the tertiary hydroxyl groups in the form of water and, if desired, subsequent partial hydrogenation which doesnct change the 45 unsaturated lactone ring. Especially suitable are 50 of peroxides, for instance benzoperacid or'hydrothe natural heart poisons themselves.

For the oxidation according to-the presentinvention various methods are available, for' example ozonization and scission oi-the ozonide, action gen peroxide, preferably in "'the' presence of i osmium tetroxide, or addition of two hydroxyl groupsat the double linking andwscission by chromic acid or lead tetracetate of the glycol thus produced. In this manner the double linking of the unsaturated lactone ring is first opened. It is also possible, however, by a more deeply seated oxidation, for example by means of a permanganate or chromic acid, t0 degrade the lactone ring directly to the carboxyl group. In. each case secondary hydroxyl groups are protected advantageously 'intermediately from the action of. the oxidation by esterification or etheri- -fication and the nuclear double linkings, for example by addition of halogen or hydrogen halide.

The acid scission of any intermediately produced fl-ketocarboxylic acid may be by the usual methods, for example by means of strong alkali or alkali alcoholate.

If the compounds of the etio-cholanic acid series thus produced contain tertiary hydroxyl groups, these may be removed in stages or completely with formation of nuclear unsaturated carboxylic acids by the action of an agent eliminating water, for example aqueous alcoholic mineral acid. The elimination oi water can also be united with the acid scission.

By hydrogenation the nuclear unsaturated compoundsmay be converted into nuclear saturated compounds. tial elimination of water, and, if desired, hydrogenation, a further elimination of water and/or hydrogenation may be added.

tion of the invention to digoxigenin.

oo-omooou If there has been only a par- 3:1l-dioxy-etio-cholanic acid If instead of di oxigenin other genins are used, other oxy-etic-cholanic and allocholanic acids may be obtained.

The products of the invention are intermediate products for the production of valuable therapeutic compounds.

The following example illustrates the invention:

1 part by weight of digoxigenin-diacetate of the formula I of melting point 221 C. is'suspended in glacial acetic acid and treated with ozone at a. low temperature. The solution is strongly coneentrated in a vacuum andthe desired product is precipitated. in the form of an oil by adding Water, and the solvent is then poured off. The oil is heated in the boilingwater bath with 2 parts of potassium hydroxide ina little alcohol of 50 per cent strength, while shaking, for several hours. The mass isthen diluted with much water and the small proportion of neutral product is extracted with ether. From the aqueous phase there is obtained by addition of an equivalentproportion of acid the crude 3211+l4-trioxy-etio-cholanic acid (III), which is not purified but is further Worked up as such. From this crude product Water is eliminated by several hours heating with a solution of sulfuric acid of 5 per cent strength in alcohol of 50 per cent strength upon the boiling'water-bath. The mass is then shaken with cold alkali lye and ether. The neutral portions dissolved by the ether are subjected again to the above treatment after saponification with causticalkali. The aqueous alkali portions which'contain the carboxyli c acid salt half dissolved and half emulsified are finally purified as .follows: The ether is expelled from the alkaline phase and the product is precipitated by means of sulfuric acid and filtered. This residue, after addition of some mineral acid, is dissolved in ether, the ethereal solution is extracted with a little alkali lye, the aqueous phase is centrifuged and the supernatant solution of nearly colorless alkali salt is siphoned off. The alkali salt is now decomposed, after e'mulsification in ether, by means of dilute sulfuric acid, the ethereal solution is dried and evaporated and from the residue there is obtained by recrystallization from glacial acetic acid or acetone pure colorless 3:11-dioxy-aetiocholenic acid (IV). The latter may be hydrogenated by means of platinum oxide in glacial acetic acid, into 3:11-dioxy-aetio-cholanic acid (V), which also may be obtained pure by recrystallization from glacial acetic acid or acetone. The digoxigenin-diacetate may be ozonized, for example by treatment with ozone in a halogenated hydrocarbon strongly cooled, and the ozonide may be split by hydrogenating with hydrogen in solution in ethyl acetate. It is also possible to arrive at 3:11:l l-trioxy-etio-cholanic acid by direct oxidation of digoxigenin-diacetate by means of a permanganate in acetone or of chromic acid in glacial acetic acid.

Instead of from digoxigenin-diacetate one may start, for instance, from l l-desoxy-digoxigenindiacetate or anhydro digoxigenin diacetate. There is thus obtained on the one hand without final water elimination and hydrogenation the 3:1l-dioxy-etio-cholanic acid, and on the other hand'the 3:ll-d-ioxy-etio-cho-lenic acid, it being advantageous before the ozonization to saturate the cyclic linking by means of 1 mol bromine. and subsequently, for example, to restore it by hydrogenation by means of zinc andglacial acetic acid, alkali iodide in alcohol or catalytically. The dioxyeetio-cholenic acid thus produced maybe hydrogenated to dioxy-etio-cholanicu'acid either simultaneously with the debromination or as a final operation.

Instead of the acetate other esters or'ethers may be.used,'for instance acylated digilanides C or digoxins.

What weclaim r l. The process for the manufacture of compounds .of the etio-cholanic acid series comprising treating a compound of .the group of genins of the heart glucosides and their esters and ethers containing in the 'l'l-position a 3, (Jr-unsaturated a-lactonering with oxidizing agents after temporary protection of free secondary nuclear hydroxyl. groups.

2. The process for the manufacture of compounds of the etio-cholanic acid series comprising treating a compound of the group" of genius o f the heartglucosides and'their esters and ethers v containing inthe 17-position a453, Lat-unsaturated a-lactone ringwith oxidizing agents after temporaryprotection of. free secondary nuclear hydroxyl groups, and finally with agents eliminatingwater for the purpose of removing tertiary of theheart-glucosidesand their esters and ethers containing in the l'Z-pcsition a 5, a-unsaturated u-lactone ring withoXidiz-ing agents after temporary protectionof free secondary nuclear hydroxyl groups, then with agents eliminating water for the purpose of removing tertiary hy-;.

droxyl groups present and :finally hydrogenating thedouble linkings thus produced.

4. The process for the manufacture ofcompounds of'the etio-cholanic acid series'comprisingtreating iacompound of the group of geninsi of the heart glucosides and their esters'and' ethers containingi'in the l'l positiona 3, a-unsaturated a-lactonezeringizwith a permanganate aftertemporary protection of free secondary nuclear hy- 5. The process for the manufacture of compounds of the etio-cholanie acid series comprising treating digoxigenin with a permanganate after temporary protection of the secondary nuclear hydroxyl groups, then with agents eliminating water for the purpose of removing the tertiary hydroxyl group and finally hydrogenating the double linking thus produced.

6. The process for the manufacture of compounds of the etio-cholanic acid series comprising treating digoxigenin with a permanganate after temporary protection of the secondary nu clear hydroxyl groups by acylation, then with agents eliminating water for the purpose of removing the tertiary hydroxyl group and finally hydrogenating the double linking thus produced.

'7. The process for the manufacture of compounds of the etio-cholanic acid series comprising treating digoxigenin with a permanganate pounds of the etio-cholanic' acid series comprising treating an unsaturated compound of the group of genins of the heart glucosides and their esters and ethers containing in the 17- position a B, a-unsaturated a-lactone ring with oxidizing agents after temporary protection of free secondary nuclear hydroxyl groups and nuclear double linkings.

9. The process for the manufacture of compounds of the etio-cholanic acid series comprising treating an unsaturated compound of the group of genins of the heart glucosides and their esters and ethers containing in the 17- position a 5, a-unsaturated a-lactone ring with oxidizing agents after temporaryprotection of free secondary nuclear hydroxyl groups by acylation and nuclear double linkings by halogen.

10. The process for the manufacture of compounds of the etio-cholanic acid series comprising treating an unsaturated compound of the group of genins of the heart glucosides and their esters and ethers containing in the 17- position a c, (at-unsaturated a-lactone ring with oxidizing agents after temporary protection of free secondary nuclear hydroxyl groups by acetylation and nuclear double linkings by bromine.

11. A process as claimed in claim 10 wherein anhydrodigo-xigenin is used as starting material.

12. The process for the manufacture of compounds of the etio-cholanic acid series comprising treating a compound of the group of genins of the heart glucosides andtheiresters and ethers containing in the 17-position a B, wunsaturated u-lactone ring with oxidizing agents after temporary protection of free secondary nuclear hydroxyl groups, and subjecting to acid scission the p-ketocarboxylic acid intermediately produced.

l3.'The process for the manufacture of com' pounds of the etio-cholanic acid series comprising treating a compound of the group of genins of the heart glucosides and their esters and ethers containing in the 1'7-position a ,6, rat-unsaturated a-lactone ring with oxidizing agents after temporary protection of free secondary nuclear hydroxyl groups, subjecting to acid scission the fi-ketocarboxylic' acid intermediately produced and finally treating with agents eliminating water for the purpose of removing tertiary hydroxyl groups present.

14. The process for the manufacture of compounds of the etio-cholanic acid series comprising treating a compound of the group of genins of the heart glucosides and their esters and ethers containing in the 17-position a 3, iii-unsaturated a-lactone ring. with oxidizing agents after temporary protection of free secondary nuclear hydroxyl groups, subjecting to acid scission the fl-ketocarboxylic acid intermediately produced, then treating with agents eliminating water for the purpose of removing tertiary hydroxyl groups present and finally hydrogenating the double linkings thus produced.

15. The process for the manufacture of compounds of the etio-cholanic acid series comprising treating a compound of the group or" genins of the heart glucosides and their esters and ethers containing in the 17-position a p, (it-unsaturated a-lactone ring with ozone after temporary protection of free secondary nuclear hydroxyl groups, subjecting to acid scission the fl-ketocarboxylic acid intermediately produced, then treating with agents eliminating Water for the purpose of removing tertiary hydroxyl groups present and finally hydrogenating the double linkings thus produced.

16. A process for the manufacture of compounds of the etio-cholanic acid series comprising treating digoxigenin with ozone after temporary protection of the secondary nuclear hydroxyl groups, subjecting to acid scission the ,B-ketocarboxylic acid intermediately produced, then treating with agents eliminating water for the purpose of removing the tertiary hydroxyl group and finally hydrogenating thedouble linking thus produced.

17. A process for the manufacture of compounds of the etio-cholanic acid series comprising treating digoxigenin with ozone after temporary protection of the secondary nuclear hy-'- droxyl groups by acylation, subjecting to acid scission the ,c-ketoc'arboxylic acid'intermediately produced, then treating with agents eliminating water for the purpose of removing the tertiary hydroxyl group and finally hydrogenating the double linking thus produced.

18. A process for the manufacture of compounds of the etio-cholanic acid series comprising treating digoxigenin with ozone after temporary protection of the secondary nuclear hydroxyl groups by acetylation, subjecting to acid scission the p-ketoc'arboxylic acid intermediately produced, then treating with agents eliminating water for the purpose of removing the tertiary hydroxyl group and finally hydrogenating the double linking thus produced.

19. The 10,13 dimethyl cyclopentanopolyhydrophenanthrene-17-carboxylic acids containing in their nucleus three members of the group consisting of hydroxyl, esterified and etherified hydroxyl,

20. The 3,11,14-trihydroxy 10,13 dimethylcyclopentanopolyhydrophenanthrene-17-carboxlyic acid.

MAX I-IARTMANN. ALBERT WETTSTEIN. 

